**5. Causes of the antibiotic resistance crisis**

#### **5.1. Overuse**

Antibiotic consumption is the single most important risk factor for emergence and spread of resistant bacterial strains. In many countries including India, antibiotics are easily available over the counter even without a prescription [28]. Moreover, antibiotics are plentiful and cheap also. This non-prescription use of drugs varies from 19 to 90% in various countries outside the United States and Europe, which is a matter of serious concern [29]. The problem has been compounded by the online purchase of these products, which further facilitate the self-medication. Some surveys reported that patients often do not know that they were prescribed an antimicrobial and the true proportion of patients using antimicrobials is probably higher than the reported [30, 31]. On the other hand, there are instances where patients demand antibiotics from their clinicians.

#### **5.2. Inappropriate prescriptions**

Incorrectly prescribed antibiotics contribute majorly to the burden of resistant bacteria. Several studies have observed that indication, choice of the antibiotics and duration of treatment are incorrect in almost 30–50% of cases [32, 33]. Extensive usage occurs in ICUs and high-dependency units, and there too approximately, 30–60% of the usage is unnecessary or incorrect [33]. Studies from pharmacies of Vietnam show that 90% of antimicrobials are sold without a proper prescription [34]. Upper respiratory tract infections (URTI) are good example, for which antimicrobial are commonly prescribed over the counter. This illustrates the overuse of antimicrobials for a condition that is often self-limiting and generally of viral aetiology. Suboptimal doses of any antibiotic further promote the genetic alterations as well as mutagenesis in the bacteria which lead to the development of multidrug resistance in them.

#### **5.3. Extensive use in livestock sector**

emergence of ESBLs among different microorganisms on global level led to widespread and increased use of carbapenems giving rise to emergence of pandemic CRE [24]. The Centers for Disease Control and Prevention has categorised CRE as *urgent* and ESBL-producing Gram-

The scale, to which antibiotic resistance has become a challenge in the treatment of the modern medicine, is scary to say the least. Every year, around 25,000 patients die of the infection with multidrug-resistant bacteria alone in the European Union [25]. In the United States alone, nearly 90,000 people die of hospital-acquired infections [26]. According to Jim O'Neill, >700,000 people die across the globe every year due to infections caused by multidrug-resistant organisms [27]. In this study, it was predicted that by 2050, more than 10 million people will die because of multidrug-resistant bugs. Huge economic losses are also expected, leading to reduction of 2–3.5% in GDP; livestock production will fall by 3–8%, costing the world up to \$100 trillion [27]. Developing countries in Africa and South Asia will be the worst affected. AMR is not only a problem of human medicine but also an ecological problem. Microbes have proved not only smarter than humans in developing new arsenal but also have armies in the form of biofilms. It looks like humans may be losing the arms race to bacteria, and the advent

Antibiotic consumption is the single most important risk factor for emergence and spread of resistant bacterial strains. In many countries including India, antibiotics are easily available over the counter even without a prescription [28]. Moreover, antibiotics are plentiful and cheap also. This non-prescription use of drugs varies from 19 to 90% in various countries outside the United States and Europe, which is a matter of serious concern [29]. The problem has been compounded by the online purchase of these products, which further facilitate the self-medication. Some surveys reported that patients often do not know that they were prescribed an antimicrobial and the true proportion of patients using antimicrobials is probably higher than the reported [30, 31]. On the other hand, there are instances where patients

Incorrectly prescribed antibiotics contribute majorly to the burden of resistant bacteria. Several studies have observed that indication, choice of the antibiotics and duration of

negative bacteria as *serious* antibiotic threats in the USA [10].

**4. The scare and complexity of antibiotic resistance**

of the post-antibiotic era is imminent.

4 Antimicrobial Resistance - A Global Threat

demand antibiotics from their clinicians.

**5.2. Inappropriate prescriptions**

**5.1. Overuse**

**5. Causes of the antibiotic resistance crisis**

Antibiotics are widely used as growth promoters and to prevent infections in the livestock sector. In the United States alone, an estimated 80% of the sold antibiotics are used in farm animals [7]. In 2010, India was one of the world's largest consumers of antibiotics in the veterinary sector [35]. The resistant bacteria reach the consumers through food animal products, mainly meat. These bacteria constitute large pools of AMR genes that can be transferred to humans and pathogenic bacteria by natural horizontal gene transfer mechanisms. These bacteria, although some may only be transient and do not colonise the intestinal tract, reside long enough to interact with the host microbiota and may possibly acquire or release genes. They can also act as opportunistic pathogens in susceptible hosts and probably play a key role in the evolution and dissemination of AMR. The use of antibiotics in food not only leads to the emergence and spread of resistant bacteria but also can be hazardous to many types of nontargeted environmental microorganisms. High concentrations of therapeutic antibiotics tend to be lethal to most bacterial strains leaving little opportunity for selection of subpopulations that have low or intermediate resistant traits. On the other hand, low levels of antibiotics in environment like soil, water and sewage become grounds for the selection of resistant microorganisms leading to the development of resistant gene pool or resistome [7, 12].

#### **5.4. Availability of few new antibiotics**

Investment in antibiotic development research is no longer considered as an economically wise decision for pharmaceutical companies [36]. According to a study conducted in London, it was calculated that the net present value (NPV) of new antibiotics is only about \$50 million, compared to approximately \$1 billion for a drug used to treat a neuromuscular disease [37].

Other reasons include low cost of antibiotics, regulatory barriers and tendency to save the new drug for serious infections. In spite of global warnings issued by many agencies, very few new drug discoveries fail to keep pace with worsening resistance scenario. As declared by the CDC in 2013, the human race is moving into a new era of infectious disease: the post-antibiotic period [38]. Here are few examples of the MDR organisms which are considered a substantial threat to the humankind. They have been divided as "urgent," "serious" or "concerning" by CDC [24, 39] (**Figure 2**).

We hope that novel hitherto unknown mechanisms of antibiotic resistance will be revealed which can be exploited to find new targets. The drugs targeting anti-virulence mechanisms are an attractive strategy and have shown some promising results. Other interesting approach may be to target/alter untapped metabolic pathways like fatty acid synthesis, proton motive force, quorum sensing, signal transduction, efflux pumps, etc. [12]. Many of such compounds

Introductory Chapter: Stepping into the Post-Antibiotic Era—Challenges and Solutions

http://dx.doi.org/10.5772/intechopen.84486

7

Some of the compounds are already approved by FDA for treatment of metabolic disorders and cancers also have antimicrobial properties and can be repurposed, e.g., the compound BPH-652 that inhibits squalene synthase involved in cholesterol biosynthesis and also inhibits dehydrosqualene synthase involved in virulence in *Staphylococcus aureus*, hence a good

The drugs used in the past, which have been revived and now are used to treat the infections caused by Gram-negative bacteria, include colistin, fosfomycin, temocillin and rifampicin [17].

Finding a suitable antimicrobial treatment option for some of the highly drug-resistant bacteria can be really daunting, and many times, clinicians resort to using combinations without data pertaining to their efficacy. The main drugs in these combinations are polymyxins and tigecycline; however, additional drugs comprise carbapenems, tigecycline, fosfomycin, aminoglycosides, and rifampicin [17] where data on randomised control trials of these drugs is also lacking. The factors which need to be taken into account before an appropriate combination is used includes the targeted organism and its susceptibility profile, co-morbidities present in the patient and the site of the infection. More studies including pharmacokinetic and

Phages have the advantage of high specificity for their hosts without any notable adverse effects. They were historically in use in Europe for treatment of bacterial infections such as skin/wound infections, urinary tract infections, ear infections and even osteomyelitis [41]. New interest has been generated in phage therapy, and it may turn out to be a useful adjunct to antibiotics. Coupling antibiotics with phages or inhibitors of enzymes appears to be an

The extent to which AMR has spread is due to the selective pressure provided by extensive antibiotic consumption and usage. Strategies to curtail the human use of antibiotic include antibiotic

candidate for Methicillin-resistant *Staphylococcus aureus* (MRSA) [12].

pharmacodynamics studies are required to find the ideal combinations [40].

attractive strategy which may succeed in many cases [41].

**7. Prevention of further spread of AMR**

are currently in experimental stages.

**6.3. Considering conventional drugs**

**6.4. Combination therapy**

**6.5. Phage therapy**

**6.2. Repurposing of compounds**

**Figure 2.** Urgent, concerning and serious threats with respect to development of antimicrobial resistance.
